Tissue adhesives and sealants have many potential medical applications, including wound closure, supplementing or replacing sutures or staples in internal surgical procedures, preventing leakage of fluids such as blood, bile, gastrointestinal fluid and cerebrospinal fluid, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives and sealants are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of viral infection. Additionally, fibrin-based adhesives do not bond covalently to the underlying tissue.
Several types of hydrogel tissue adhesives have been developed, which have improved adhesive and cohesive properties and are nontoxic (see for example Sehl et al., U.S. Patent Application Publication No. 2003/0119985, and Goldmann, U.S. Patent Application Publication No. 2005/0002893). These hydrogels are generally formed by reacting a component having nucleophilic groups with a component having electrophilic groups that are capable of reacting with the nucleophilic groups of the first component to form a crosslinked network via covalent bonding. However, these hydrogels typically swell, dissolve away too quickly, or lack sufficient adhesion or mechanical strength, thereby decreasing their effectiveness as surgical adhesives.
Kodokian et al. (copending and commonly owned U.S. Patent Application Publication No. 2006/0078536) describe hydrogel tissue adhesives formed by reacting an oxidized polysaccharide with a water-dispersible, multi-arm polyether amine. These adhesives provide improved adhesion and cohesion properties, crosslink readily at body temperature, maintain dimensional stability initially, do not degrade rapidly, and are nontoxic to cells and non-inflammatory to tissue. However, the instability of oxidized polysaccharides in aqueous solution limits their shelf-life for commercial use. For example, dextran aldehyde undergoes hydrolytic depolymerization much more rapidly than its parent polymer, dextran (E. Schacht et al. J. Controlled Release, 1:33-46, 1984; Callant at al. Reactive Polymers, 8: 129-136, 1988).
Therefore, the need exists for a tissue adhesive and sealant that has the desirable properties of the hydrogel tissue adhesive described by Kodokian et al., supra, but that is formed using a polymer containing aldehyde groups that is more stable in aqueous solution than oxidized polysaccharides. The need also exists for a tissue adhesive and sealant that comprises a polymer containing aldehyde groups, which is more stable in aqueous solution than oxidized polysaccharides, and that has an adhesive strength that is similar to or greater than those of comparable formulations produced with an oxidized polysaccharide.